A novel therapeutic strategy targeting HMGB1 isoforms in sepsis
| Project/Area Number |
18H02904
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 55060:Emergency medicine-related
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| Research Institution | Kagoshima University |
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Principal Investigator |
ITO Takashi 鹿児島大学, 医歯学総合研究科, 特任准教授 (20381171)
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| Co-Investigator(Kenkyū-buntansha) |
丸山 征郎 鹿児島大学, 医歯学総合研究科, 特任教授 (20082282)
垣花 泰之 鹿児島大学, 医歯学域医学系, 教授 (20264426)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2020: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2018: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
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| Keywords | 敗血症 / 核内タンパク質 / DAMPs / アイソフォーム / 抗体 / トロンボモジュリン / 播種性血管内凝固（DIC） / HMGB1 / 治療 / 診断 / メディエーター / 組織損傷 |
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| Outline of Final Research Achievements |
During sepsis, high mobility group box 1 protein (HMGB1) can be released from the cellular nucleus to the extracellular space. Extracellular HMGB1 acts as a signal of tissue damage and promotes not only inflammatory responses but also tissue regeneration. Recent studies have suggested that disulfide HMGB1 promotes inflammation whereas all-thiol HMGB1 promotes tissue regeneration. However, to date, there is no reliable way to differentially target these HMGB1 subtypes. In this research project, we have identified monoclonal antibodies that can discriminate between inactive HMGB1 and active HMGB1. We have also obtained a neutralizing antibody against HMGB1 that shows a significant survival benefit over the control antibody in mice with cecal ligation and puncture-induced sepsis. These antibodies may be useful for the in-depth analysis of HMGB1-induced pathogenicity as well as HMGB1-targeting therapy.
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| Academic Significance and Societal Importance of the Research Achievements |
本邦では敗血症によって年間およそ10万人が命を落としていると推定されている。早期診断と集中治療によって生存率の改善が期待できるが、敗血症に対する特異的な治療法は確立されていない。細胞外に放出された核内タンパク質HMGB1は、有望な治療標的と考えられていたが、良い働きと悪い働きを併せ持ったタンパク質であるが故に、これまで十分な有用性が発揮されずにいた。本研究において、良い働きをするHMGB1と悪い働きをするHMGB1を区別しうるモノクローナル抗体を獲得できたことにより、敗血症の病態把握と新規治療戦略構築が進み、敗血症の生存率改善に寄与できる可能性が考えられる。
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Report
(4 results)
Research Products
(25 results)
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[Journal Article] Loss of Endogenous HMGB2 Promotes Cardiac Dysfunction and Pressure Overload-Induced Heart Failure in Mice2019
Author(s)
Sato M, Miyata K, Tian Z, Kadomatsu T, Ujihara Y, Morinaga J, Horiguchi H, Endo M, Zhao J, Zhu S, Sugizaki T, Igata K, Muramatsu M, Minami T, Ito T, Bianchi ME, Mohri S, Araki K, Node K, Oike Y
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Journal Title
Circulation Journal
Volume: 83
Issue: 2
Pages: 368-378
DOI
NAID
ISSN
1346-9843, 1347-4820
Year and Date
2019-01-25
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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